The liver, both in humans and in animals, has the unique capacity of regulating its growth and its weight. If a harmful agent destroys part of the hepatic parenchyma, the surviving hepatocytes are able to replicate and thus replace the damaged parenchyma. If hepatic resection or hepatocellular lesion of viral, toxic, immunologic or metabolic origin affects a very high proportion of the parenchyma so that the regenerative capacity of the hepatic tissue that remains is exceeded, a hepatic insufficiency develops which can prove fatal. At present, no drug exists with liver-protecting and regeneration-stimulating effect that can be used in acute or chronic hepatic insufficiency. It is therefore urgent and important that the array of drugs used in hepatology should include therapeutic products for these indications. An hepatoprotective agent is a product or active principle able to protect hepatic cells against a variety of stimuli causing toxicity and/or damage in hepatocytes and ultimately necrosis or apoptosis. Thus, whenever liver damage is induced, the administration of hepatoprotective agents at the right doses will improve the survival of hepatic cells facilitating hepatic regeneration, contributing to liver function normalization and in extreme cases, to the survival of the individual. Liver damage can be induced by toxic agents (including alcohol), viruses, autoimmune disorders, ischemia, ischemia/reperfusion (as in the case of the damage induced in the liver implanted during liver transplantation) and in general by any inflammatory processes. A good hepatoprotective agent will preclude or decrease the development of liver damage and hepatic cell death in those situations.
By liver regeneration we understand the reaction of the liver to compensate a decrease in its functional mass (either decrease in tissue or cells loss) by the proliferation of normal hepatocytes until the liver mass is restored. There are several clinical settings in which liver regeneration plays an important role, including hepatic resection during surgery (partial hepatectomy or liver transplantation by live donors) or situations of liver damage as described above (toxic agents, viruses, ischemia, ischemia/reperfusion, etc). A stimulating agent of liver regeneration is an agent able to induce such hepatocellular proliferation, helping to reduce mortality related with functional mass decrease.
The present invention proposes the use of cardiotrophin in liver diseases.
Cardiotrophin (also called CHF or cardiac hypertrophy factor) has been employed previously in the treatment of cardiac disorders and neurodegenerative and neurologic diseases (WO 95/29237), as a modulator of local inflammatory processes linked to the LIFRβ receptor (WO 97/30146), in the diagnosis and treatment of tumors (WO 00/43790), and in the treatment of amyotrophic lateral sclerosis and Parkinson's disease (WO 97/39629).
The invention does not relate to any of these applications, but focuses on the uses of CT-1 in therapeutic compositions that can be used in the treatment of hepatocytes, and especially as an agent for protecting the latter against processes of apoptosis and necrosis and as an agent for stimulating hepatic regeneration in general.
CT-1 is one of the so-called neuropoietic cytokines belonging to the IL-6 family (1). The receptors of the cytokines of this family are made up of distinct subunits, but they all share the gp130 subunit (2). Some members of the family (IL-6 and IL-11) induce homodimerization of gp130 (3), whereas others such as leukemia inhibitory factor (LIF), oncostatin and ciliary neurotrophic factor (CNTF) induce heterodimerization of the gp130 subunit with the 190 kDa LIF receptor (4). The CT-1 receptor contains the gp130 chain, the β subunit of the LIF receptor (LIFRβ) and a third component known as the α subunit of the CT-1 receptor (5, 6). The latter participates in the formation of a three-part complex that confers high sensitivity and specificity to CT-1. Activation of the CT-1 receptor induces a series of intracellular signals that include the early activation of tyrosine kinases of the JAK family (JAK-1, JAK-2 and Tyk2). The main effectors of the JAKs are the group of cytosolic transcription factors STATs (STAT-1 and STAT 3; signal-transducing activators of transcription). Activation of the JAKs also signals via the Ras-MAP kinase pathway and is involved in activation of the PI3-K (phosphatidyl inositol 3-kinase) pathway (2).
CT-1 was originally identified as a hypertrophic factor in cardiomyocytes (7, 8) as it had been shown to have a role in stimulating the embryonic development of cardiomyocytes and a protective action on cardiomyocytes against apoptosis induced by hypoxia, ischemia, and damage by ischemia-reperfusion and (8, 9, 10, 11, 12). A protective effect on the myocardium has also been described in cases of heart failure (10). Other effects of CT-1 include promotion of the survival of motoneurons and dopaminergic neurons (13, 14).